Oxacillin

OXACILLIN- oxacillin sodium injection, powder, for solution
Armas Pharmaceuticals Inc.

R x only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of oxacillin for injection and other antibacterial drugs, oxacillin for injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Oxacillin for Injection, USP is a semisynthetic penicillin antibiotic derived from the penicillin nucleus, 6-amino-penicillanic acid. It is resistant to inactivation by the enzyme penicillinase (beta-lactamase). It is the sodium salt in parenteral dosage form for intramuscular or intravenous use.

Each vial of oxacillin for injection, USP contains oxacillin sodium monohydrate equivalent to 1 gram or 2 grams of oxacillin. The sodium content is 57.4 mg (2.5 mEq) per gram oxacillin. The product is buffered with 20 mg dibasic sodium phosphate per gram oxacillin. Oxacillin for injection, USP is white to off white powder and gives a clear solution upon reconstitution.

OXACILLIN SODIUM

Structure
(click image for full-size original)

The chemical name of oxacillin sodium is 4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 3,3-dimethyl-6-[[(5-methyl-3-phenyl-4-isoxazolyl)carbonyl]-amino]-7-oxo-, monosodium salt, monohydrate, [2S-(2α,5α,6β)]-. It is resistant to inactivation by the enzyme penicillinase (beta-lactamase). The molecular formula of oxacillin sodium is C 19 H 18 N 3 NaO 5 S•H 2 O. The molecular weight is 441.43.

CLINICAL PHARMACOLOGY

Intravenous administration provides peak serum levels approximately 5 minutes after the injection is completed. Slow I.V. administration of 500 mg gives a peak serum level of 43 mcg/mL after 5 minutes with a half-life of 20 to 30 minutes.

Oxacillin sodium, with normal doses, has insignificant concentrations in the cerebrospinal and ascitic fluids. It is found in therapeutic concentrations in the pleural, bile, and amniotic fluids.

Oxacillin sodium is rapidly excreted as unchanged drug in the urine by glomerular filtration and active tubular secretion. The elimination half-life for oxacillin is about 0.5 hours. Nonrenal elimination includes hepatic inactivation and excretion in bile.

Oxacillin sodium binds to serum protein, mainly albumin. The degree of protein binding reported varies with the method of study and the investigator, but generally has been found to be 94.2 ± 2.1%.

Probenecid blocks the renal tubular secretion of penicillins. Therefore, the concurrent administration of probenecid prolongs the elimination of oxacillin and, consequently, increases the serum concentration.

Intramuscular injections give peak serum levels 30 minutes after injection. A 250 mg dose gives a level of 5.3 mcg/mL while a 500 mg dose peaks at 10.9 mcg/mL. Intravenous injection gives a peak about 5 minutes after the injection is completed. Slow IV dosing with 500 mg gives a 5 minute peak of 43 mcg/mL with a half-life of 20 to 30 minutes.

MICROBIOLOGY

Mode of Action

Penicillinase-resistant penicillins exert a bactericidal action against penicillin susceptible microorganisms during the state of active multiplication. All penicillins inhibit the biosynthesis of the bacterial cell wall.

Mechanism of Resistance

Resistance to penicillins may be mediated by destruction of the beta-lactam ring by a beta-lactamase, altered affinity of penicillin for target, or decreased penetration of the antibiotic to reach the target site.

Cross Resistance

Resistance to oxacillin (or cefoxitin) implies resistance to all other beta-lactam agents, except newer agents with activity against methicillin-resistant Staphylococcus aureus.

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antibacterial drug for treatment.

Dilution techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method 1,2 (broth and/or agar). The MIC values should be interpreted according to the criteria in Table 1.

Diffusion techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized method. 2,3. It has been determined that the most accurate method to test the susceptibility of microorganisms to penicillinase resistant penicillins, including oxacillin, by disk diffusion is achieved using disks impregnated with 30 mcg cefoxitin. Interpretation involves correlation of the diameter obtained with the cefoxitin disk test with the MIC for oxacillin 2. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 microgram cefoxitin disk should be interpreted according to the following criteria in Table 1.

Table 1: Susceptibility Test Interpretive Criteria for Oxacillin

Pathogen Antimicrobial Disk Disk Diffusion Zone Diameter Minimum Inhibitory
Agent Content (mm) a Concentrations (mcg/mL)
S I R S I R
Staphylococcus
aureus and
S. lugdenensis c
Oxacillin ≤ 2

(oxacillin)

≥ 4

(oxacillin)

30 mcg
cefoxitin b
≥ 22 ≤ 21 ≤ 4

(cefoxitin)

≥ 8

(cefoxitin)

Coagulase-
negative
Staphylococci
except
S. lugdenensis
Oxacillin d ≤ 0.25 ≥ 0.5
30 mcg
cefoxitin b
≥ 25 ≤ 24

S=susceptible, I=intermediate, R=resistant

a In most staphylococcal isolates, oxacillin resistance is mediated by mecA, encoding the penicillin binding protein 2a (PBP2a, also called PBP2′). Isolates that test positive for mecA or PBP2a should be reported as oxacillin resistant.”

2b Cefoxitin is used as a surrogate for oxacillin; report oxacillin susceptible or resistant based on the cefoxitin result.

2c If both cefoxitin and oxacillin are tested against S. aureus or S. lugdenensis , and either result is resistant, the organism should be reported as oxacillin resistant.

2d Oxacillin MIC interpretive criteria may overcall resistance for some coagulase-negative staphylococci (CoNS), because some non-S. epidermidis strains for which the oxacillin MICs are 0.5 to 2mcg/ml lack mecA. For serious infections with CoNS other than S. epidermidis, testing for mecA or for PBP 2a or with cefoxitin disk diffusion

A report of “Susceptible” indicates that the antimicrobial is likely to inhibit the growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of “Intermediate” indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test. 1,2,3 Standard oxacillin powder should provide the following range of MIC values 1 noted in Table 2. For the diffusion technique using the 30 mcg cefoxitin disk, the criteria in Table 2 should be achieved.

Table 2. Acceptable Quality Control Ranges for Susceptibility Testing*

Quality Control

Organism

Minimum Inhibitory Concentration

(mcg/mL)

Disk Diffusion Zone

Diameters (mm)

Enterococcus faecalis

ATCC ® 29212

8-32
Staphylococcus aureus

ATCC ® 25923

18-24
Staphylococcus aureus
ATCC ® 29213
0.12 — 0.5
Streptococcus

pneumonia

ATCC ® 49619 a

≤12 b

ATCC=American Type Culture Collection

a Despite the lack of reliable disk diffusion interpretive criteria for S. pneumoniae with certain beta-lactams, Streptococcus pneumonia ATCC ® 49619 is the strain designated for QC of all disk diffusion tests with Streptococcus spp.

b Deterioration of oxacillin disk content is best assessed with QC organisms S. aureus ATCC ® 25923, with an acceptable zone diameter for 18-24.

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